The underlying etiological basis for vascular diseases, such as myocardial infarct, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion and other venous thromboses, is either a partial, or total occlusion of a blood vessel by a blood clot-thrombus or thromboembolus. These diseases were traditionally treated with anti-coagulants, such as heparin and coumarin. These antithrombogenic agents inhibit thrombus formation. Traditional anticoagulant therapy, however, does nothing to directly enhance dissolution of thrombi or thromboemboli. More recently, therapy, particularly for acute episodes of these diseases, involves the use of thrombolytic agents, such as urokinase, streptokinase, and tissue plasminogen activator, which break up the formation of thrombus in the vascular system of a patient.
In maintaining an intact patent vascular bed, the fibrinolytic system is in dynamic equilibrium with the coagulation system. The coagulation system deposits fibrin as a matrix serving to restore a hemostatic condition; whereas, the fibrinolytic system removes the fibrin network after the hemostatic condition is achieved. The fibrinolytic process is brought about by the proteolytic enzyme plasmin that is generated from plasminogen, which is converted to plasmin through activation by an activator, such as tissue plasminogen activator (TPA), streptokinase and urokinase. It has been found that early intervention with these compounds for incidents of acute vascular diseases such as myocardial infarct, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion and other venous thromboses, improves survival.
For treatment of cardiovascular disorders and prevention of myocardial infarction, strokes and other such disorders, it is often desirable to treat with a combination of a thrombolytic and anti-thrombotic drugs. Thus, not only are thrombolytic drugs and other treatments needed to keep the vessels in a sustained state of patency, it is critical to also employ anti-thrombotic drugs.
Opening up blocked vessels with thrombolytic drugs and/or angioplasty can be achieved, but does not prevent re-occlusion of the vessel, either from formation of additional thromboses or from restenosis. Atherosclerosis, sometimes referred to as arteriosclerosis, results from the development of an intimal lesion and the subsequent narrowing of the vessel lumen. Commonly, atherosclerosis originally appears as a result of the buildup of plaque which lines the interior of blood vessels, particularly the arteries. Whereas bypass surgery is sometimes employed to replace such clogged arteries, in recent years, a number of surgical procedures have been developed so as to interarterially remove such plaque, often by balloon catheterization or other such treatments in which the plaque is either compressed against or scraped away from the interior surface of the artery. Not infrequently, re-narrowing of the vessel lumen reoccurs in a relatively short period after treatment. This re-narrowing, generally referred to as restenosis, requires a repetition of the surgical procedure to remove the increasing blockage. There is a need exists for preventing such recurrence in patients who have been treated for atherosclerosis.